1. Field of the Invention
The field of this invention comprises aqueous solutions of nitroglycerin that are intended for intravenous injection, processes for making such solutions, and the use of such solutions in the treatment of humans and other mammals, especially for treating cardiovascular disease.
2. Description of the Related Art Including Information Disclosed Under 37 C.F.R. .sctn..sctn.1.97-1.99 (1987).
Aqueous nitroglycerin injection is a comparatively recent development. Although nitroglycerin has been used medically for over 100 years, and is administered today in a wide variety of forms, including sublingual tablets, cutaneous ointments and creams, transdermal pads, and intravenous injection solutions, injectable solutions have been in use for less than about 20 years. The comparatively recent development of nitroglycerin for injection may be explained in part by the sensitivity of nitroglycerin to percussive shock and its violent explosive properties upon detonation. A brief history of nitroglycerin's discovery will aide an understanding of the constraints imposed on the manufacture of aqueous nitroglycerin injection.
The name "nitroglycerin" can be used to refer to any nitrate of glycerol, but especially the trinitrate, the heavy, oily, explosive liquid invented in 1846 by Ascanio Sobrero. Nitroglycerin, or glycerol trinitrate, is also known chemically as 1,2,3-propanetriol; glyceryl trinitrate; glycerol nitric acid triester; nitroglycerol; trinitroglycerol; trinitrin; and glonoin; but is more descriptively called "blasting oil." ##STR1##
The stable form of nitroglycerin crystals melts in the temperate region of 55.4.degree. F. (13.degree. C.) and is extremely unstable as it thaws; liquid nitroglycerin will detonate if subjected to intense heat or percussion. Nitroglycerin is therefore most useful when its explosive properties are controlled, often by dispersing the compound in an inert substance. In 1867, Alfred Nobel mixed nitroglycerin with a nonexplosive, nonreactive, porous, siliceous earth, kieselguhr, and patented dynamite. While today's dynamite contains no pure nitroglycerin because it is too sensitive, pure nitroglycerin is readily available today for medical uses as an adsorbate in lactose powder.
The subsequent discovery of nitroglycerin's medical uses did not lessen its sensitivity to detonation by intense heat or shock. Although nitroglycerin is not used medically in explosive concentrations, it was the primary explosive ingredient of dynamite, and nitroglycerin's explosive properties control the commercial manufacture of drugs in which "blasting oil" is the active ingredient.
Nitroglycerin is an organic nitrate and, although poisonous if taken in large doses, in medical applications has the action of nitrites and is a vasodilator, widening the lumen, or cavity, of blood vessels. Nitroglycerin relaxes vascular smooth muscle tissue. Veins are dilated more than arteries, but both can be dilated depending on the dose. Dilation of the veins causes peripheral pooling of blood and decreases its return to the heart, reducing diastolic blood pressure. Relaxation of the arteries reduces resistance to blood flow from the heart, decreasing systolic blood pressure. Nitroglycerin is therefore excellent for opening temporarily clogged arteries during a heart attack, especially congestive heart failure associated with acute myocardial infarction. The arterial and venous effects of nitroglycerin reduce myocardial oxygen consumption, increasing oxygenation of the middle muscular layer of the heart, and nitroglycerin is therefore also useful for treating angina pectoris. Nitroglycerin finds additional utility in (1) controlling blood pressure in perioperative hypertension, or hypertension resulting from intratracheal intubation, anesthesia, skin incision, sternotomy, cardiac bypass, and postsurgical recovery, and (2) in producing controlled hypotension (induced low blood pressure) during surgery.
Just as Nobel made nitroglycerin more tractable in 1867 by dispersing the oil in kieselguhr, to make it less sensitive to shock, so mixing nitroglycerin in a lactose powder renders nitroglycerin safe to use: dynamite can be cut safely with a knife; nitroglycerin powders are easily transported. The danger lies in processing: If pure nitroglycerin separates out of the mixture then an explosion can occur. Accordingly, aqueous nitroglycerin injection has not been easily developed because of the attendant phase separation problems that can result in a pure nitroglycerin coming out of solution.
Nitroglycerin is only slightly soluble in water. Nitroglycerin, an oil, dissolves slowly in water, having a saturation concentration of only 1.25 milligrams of nitroglycerin per milliliter of water. The diffusivity of nitroglycerin in dilute solution in the solvent water at 20.degree. C., a measure of the rate at which nitroglycerin molecules will intermingle with water molecules as a result of their spontaneous movement caused by thermal agitation, is only about 0.6.times.10.sup.-5 square centimeters per second, as given by the empirical correlation of Wilke and Chang. Wilke, C.R.: Chem. Eng. Progr., 45, 218 (1949) and Wilke, C. R., and P. Chang: AIChEJ. 1, 264 (1955). Not surprisingly then, the first commercial nitroglycerin solution for injection came on the market a scant 6 years ago, in 1981.
Several formulations of nitroglycerin injection are known in the art. The 1987 PHYSICIANS DESK REFERENCE.RTM., available from Medical Economics Co, Inc., at Oradell, New Jersey, 07649, discloses at least 4 companies that make or distribute nitroglycerin solutions for intravenous use. These products are sold under the tradenames TRIDIL.RTM., NITRO-BID IV.RTM., NITROSTAT IV.RTM., and NITROL IV.RTM.. These are all concentrated drugs, not intended for direct intravenous injection, and each contains undesirable organic solvents. Each milliliter of TRIDIL.RTM. contains either alcohol or alcohol and prcpylene glycol; each milliliter of NITRO-BID IV.RTM. contains 45 milligrams propylene glycol dissolved in 70% ethanol; each milliliter of NITROSTAT IV.RTM. contains 5% alcohol; each milliliter of NITROL IV.RTM. contains dehydrated alcohol. These are all concentrated drugs that, when diluted, are chemically stable for only about 1 week, if refrigerated. The PDR.RTM. discloses no commercially available aqueous nitroglycerin solution for injection that is stable for commercial purposes and contains no organic solvent such as alcohol or propylene glycol, which is undesirable for the patient. Stability for commercial purposes is at least 12 months, and, preferably, 24 months.
The patents that claim solutions of nitroglycerin teach that organic solubilizing agents are necessary in the processing of nitroglycerin to produce injection solutions. U.S. Pat. No. 4,323,577, issued Apr. 6, 1982, to Ohkuma et al., discloses a solution of nitroglycerin in the range of 0.1 to 1 milligrams of nitroglycerin per milliliter of solution, having at least one substance selected from among the sugars sorbitol, mannitol, and xylitol in the range of from 25 to 150 milligrams per milliliter of solution. Ohkuma et al. prepare the solution by first dissolving nitroglycerin in a volatile organic solvent such as ethanol, and then mixing the solution with a powder of sorbitol, mannitol, or xylitol, or a mixture of these. The ethanol is driven off, and the powder obtained thereby, containing 0.06 to 4% by weight of nitroglycerin, can be dissolved in water with stirring at high speed to develop the aqueous solution of nitroglycerin. Ohkuma et al. cites no danger of explosion and a high degree of stability for up to eight and one-half months. The solution becomes injectable if either filtered and sterilized by heat or filtered through a GS millipore filter. The solution can be used directly or can be mixed with an infusion solution.
Ohkuma et al. specifically teach away from the use of lactose powder containing nitroglycerin. Ohkuma teaches that intravenous nitroglycerin solutions prepared from a lactose powder have a low degree of stability for storage due to the presence of lactose. Furthermore, they relate that it is difficult to obtain any lactose warranted for the absence of pyrogen, or fever inducing substances, and the presence of antigenicity since lactose available in Japan is not intended for injection.
U.S. Pat. No 4,481,220, issued Nov. 6, 1984, to Giesselmann et al., discloses a preparation of nitroglycerin that can be dissolved in water to form an isotonic nitroglycerin solution that is free of ethanol. Giesselmann made a "nitroglycerin solution having a concentration of approximately 1 mg of nitroglycerin/ml of solution without the separation of nitroglycerin droplets, by providing a small amount of a[n organic]solubilizer customarily used for parenteral administration in conjunction with a solid nitroglycerin carrier," such as lactose. Col. 5, 11. 13-18. Giesselmann et al. disclose a list of organic solvents including alcohols, ethers, and acids.
Giesselmann et al. teach that it is impossible to manufacture aqueous injection on an industrial scale without resort to the use of organic solubilizers. See Col. 4, 1. 65 through Col. 5, 1. 6. Giesselmann et al. teach that where nitroglycerin is introduced into water on a water-soluble carrier the carrier dissolves and leaves a high local concentration of nitroglycerin above its saturation point. The droplets of oil coalesce and the danger of explosion that results makes the use of this process impossible for the manufacture of nitroglycerin solutions on an industrial scale. Giesselmann et al. of course solve this problem by the addition of organic solubilizing agents.
Hospital pharmacies can make extemporaneous nitroglycerin solutions by one of three methods: (1) dissolving nitroglycerin-containing sublingual tablets in water for injection, (2) dissolving commercially supplied lactose powder containing ten percent nitroglycerin in water for injection, or (3) diluting a commercially available nitroglycerin solution for intravenous injection.
Sublingual tablets contain nonvolatile organic solvents and excipients that affect dissolution and stability. For example, U.S. Pat. No. 3,873,727 issued Mar. 25, 1975, to Fusari et al. claims a process for making molded sublingual tablets where the stability of the tablets is improved by using an organic solvent such as polyethylene glycol in combination with a water soluble pharmaceutical carrier. Dissolution of such a tablet to form an injectable solution incorporates the organic solvent in the intravenous formulation. Furthermore, the USP specification for the content of sublingual nitroglycerin tablets is 80 to 120% of the labeled strength. Preparations of nitroglycerin injection made from sublingual tablets therefore vary substantially in potency.
Commercially available nitroglycerin solutions, such as those described in the PDR.RTM., contain alcohol, organic solvents, or both, as discussed above. These solvents are present in any of the extemporaneously produced hospital formulations made by diluting commercial injection.
One solvent-free aqueous nitroglycerin injection is known that can be produced in a hospital pharmacy. In July of 1985 the American Journal of Hospital Pharmacy reported that a hospital pharmacy can create an injectable nitroglycerin solution that is stable for up to 70 days and is free of organic solvents such as ethanol or propylene glycol by dissolving a powder that contains one part nitroglycerin and nine parts lactose in normal saline (0.9% sodium chloride) or 5% dextrose for injection. Clark, Allan J. and Raymond E. Watkins. Nitroglycerin Injection Manufactured By a Hospital Pharmacy. Am J. Hosp. Pharm. 1985; 42: 1542-1546. The authors used a commercial powder adsorbate of nitroglycerin, 10% nitroglycerin and lactose, hydrous, USP, manufactured by ICI Americas, Inc., Wilmington, Del. 19897 After weighing the powder, it was placed in a 12 liter glass mixing flask, half filled with either 0.9% sodium chloride injection, USP, or 5% dextrose injection, USP. The lactose was dissolved by swirling the solution to create a pearl of nitroglycerin on the bottom of the flask. After adding a quantity of the base solution sufficient to bring the mixture to final volume, the mixture was stirred with a Lightnin' Stirrer, Series 20, which is a high speed mixer manufactured by VWR Scientific, Inc., for no less than 90 minutes.
Despite the development of a solvent-free aqueous nitroglycerin injection on a laboratory scale in a hospital pharmacy, no disclosure is made of such an injection that is producible on a commercial scale with a commercially useful shelf-life. Nitroglycerin saturates water at a concentration of only 1.25 milligrams per milliliter. Even when dispersed in lactose at a concentration of 10% nitroglycerin, the nitroglycerin is difficult to dissolve in water. The lactose dissolves immediately, leaving nitroglycerin oil droplets which quickly coalesce and result in a high local concentration of nitroglycerin above its saturation point. On a laboratory scale, such as a hospital pharmacy, where small batches of injection are prepared, the low solubility of nitroglycerin in water presents little difficulty. The lab technician simply dissolves the nitroglycerin pearl in the water/lactose solvent using a high speed mixer. It is not, however, possible to manufacture nitroglycerin solutions on an industrial scale using this process.
Until now, no method existed for making an aqueous solution of nitroglycerin, which is sterile, of adjustable tonicity, nonpyrogenic, directly injectable (ready-to-use) and dilutable, free of undesirable organic solvents, stable for at least 1 year and preferably for 2 years, and producible in a manner that is commercially useful. Salt or sugar may be added according to the needs of the patient at the time of the infusion. Dilution is a function of the fluid requirements of the patient, the expected duration of the infusion, and the responsiveness to the drug of the individual patient. There is no fixed optimum dose of nitroglycerin. Each patient must be titrated to the desired level of hemodynamic function, taking into account electrolyte requirements as well as the ability to metabolize sugars.
This invention provides a nitroglycerin solution that can be adapted to the individual patient's needs, that can be prepared on an industrial scale, that has a commercially useful shelf-life, and that contains no harmful organic solvents. Nitroglycerin is a highly explosive substance; the most advanced methods of hospital pharmacies are not safe enough to use on an industrial scale because they allow nitroglycerin to reach local concentrations above saturation.
Accordingly, it is an object of this invention to provide an aqueous solution of nitroglycerin that is suitable for intravenous injection and is stable for at least 1 year and preferably for 2 years. It is a further object of this invention to provide a nitroglycerin solution that is suitable for injection and can be adjusted for tonicity depending on the hemodynamic and fluid requirements of the individual. It is still another object of this invention to provide a ready-to-use and solvent-free aqueous solution of nitroglycerin that is adjusted for tonicity in that the base solution contains either saline or dextrose for injection.
Yet another object of the invention is to develop a process that is safe enough to be used commercially to manufacture aqueous solutions of nitroglycerin that contain no organic solvents and are stable for at least 1 year and preferably for 2 years.